Combination　therapy　through　colon-targeted　oral　delivery　of　multiple　drugs　presents　a　promising　approach　for　effectively　treating　ulcerative　colitis　(UC).　However,　the　codelivery　of　drugs　with　diverse　physicochemical　properties　in　a　single　formulation　remains　a　formidable　challenge.　Here,　microcapsules　are　designed　based　on　hydroxyethyl　starch–curcumin　(HES─CUR)　conjugates　to　enable　the　simultaneous　delivery　of　hydrophobic　dexamethasone　acetate　(DA)　and　hydrophilic　cefazolin　sodium　(CS),　yielding　multiple　drug-loaded　microcapsules　(CS/DA-loaded　HES─CUR　microcapsules,　CDHC-MCs)　tailored　for　colon-targeted　therapy　of　UC.　Thorough　characterization　confirms　the　successful　synthesis　and　exceptional　biocompatibility　of　CDHC-MCs.　Biodistribution　studies　demonstrate　that　the　microcapsules　exhibit　an　impressive　inflammatory　targeting　effect,　accumulating　preferentially　in　inflamed　colons.　In　vivo　experiments　employing　a　dextran-sulfate-sodium-induced　UC　mouse　model　reveal　that　CDHC-MCs　not　only　arrest　UC　progression　but　also　facilitate　the　restoration　of　colon　length　and　alleviate　inflammation-related　splenomegaly.　These　findings　highlight　the　potential　of　colon-targeted　delivery　of　multiple　drugs　within　a　single　formulation　as　a　promising　strategy　to　enhance　UC　treatment,　and　the　CDHC-MCs　developed　in　this　study　hold　great　potential　in　developing　novel　oral　formulations　for　advanced　UC　therapy.　©　2023　Wiley-VCH　GmbH.